CN112592330A - Synthesis method of 2-aldehyde thiochromone compound - Google Patents

Synthesis method of 2-aldehyde thiochromone compound Download PDF

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CN112592330A
CN112592330A CN202011470888.7A CN202011470888A CN112592330A CN 112592330 A CN112592330 A CN 112592330A CN 202011470888 A CN202011470888 A CN 202011470888A CN 112592330 A CN112592330 A CN 112592330A
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thiochromone
aldehyde
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dimethyl acetal
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柴永海
孙陶陶
张琦
王荣欣
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Shaanxi Normal University
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    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a method for synthesizing 2-aldehyde thiochromone, which comprises the steps of taking 2-methyl thiochromone compounds as raw materials, firstly reacting with N, N-dimethyl formamide dimethyl acetal to generate enamine intermediates, carrying out simple post-treatment on a reaction system, and directly adding a high iodine compound to carry out redox reaction to obtain the 2-aldehyde thiochromone compounds. The synthesis method has the advantages of simpler post-treatment operation, higher product yield, good repeatability and wide substrate application range, and the used N, N-dimethylformamide dimethyl acetal and the used high-iodine compound are relatively safer, so the synthesis method is simpler and more efficient.

Description

Synthesis method of 2-aldehyde thiochromone compound
Technical Field
The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of a 2-aldehyde thiochromone compound.
Background
According to Kakiuchi group (Chemical Communications,2008, 2013-. The 2-aldehyde thiochromone compound is an essential intermediate for synthesizing S, S-thiochromone photo-protecting groups of the formulas IV and V (the following formula is an equation for synthesizing the S, S-thiochromone photo-protecting group from the 2-aldehyde thiochromone). Therefore, the efficient synthesis of the 2-aldehyde thiochromone compound has important significance for the development of the thiochromone light protecting group.
Figure BDA0002833853630000011
The preparation of 2-aldehyde thiochromone compounds has been reported previously, and the U.S. Pat. No. 4, 20110028738, 1 uses 2-methyl thiochromone as a raw material, and the 2-aldehyde thiochromone compound is obtained by refluxing for 12h under the conditions that selenium dioxide is used as an oxidant and chlorobenzene is used as a solvent. The Zhang group (Heterocycles,2011,85,2337-2342.) further improves the method, and still uses 2-methyl thiochromone as a raw material, selenium dioxide as an oxidant and o-dichlorobenzene as a solvent for reflux reaction, under the condition, the product is easy to generate intramolecular Friedel-Crafts side reaction, the experimental repeatability is poor, and a large amount of byproduct selenium is still difficult to separate.
In summary, the methods for synthesizing 2-aldehyde thiochromone compounds reported at present still have some disadvantages, such as complicated separation of byproducts, unstable yield, etc. Therefore, the development of a method with higher yield, simple and convenient operation and good repeatability has important value.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2-aldehyde thiochromone compounds, which has high yield, strong repeatability and simple and convenient operation.
Aiming at the purposes, the synthesis method of the 2-aldehyde thiochromone compound adopted by the invention comprises the following steps: dissolving a 2-methyl thiochromanone compound shown in a formula I and N, N-dimethylformamide dimethyl acetal in a solvent 1, and stirring and reacting for 3-10 h at 100-170 ℃ to obtain an enamine intermediate II; and dissolving the enamine intermediate II and the high iodine compound in a solvent 2, and stirring at room temperature for 1-5 h to obtain the 2-aldehyde thiochromone compound shown in the formula III.
Figure BDA0002833853630000021
In the formula Ar1Represents phenyl, C1～C6Alkyl-substituted phenyl, C1～C6Any one of alkoxy substituted phenyl and halogenated phenyl; r1Represents hydrogen, halogen, phenyl, C1～C6Alkyl-substituted phenyl, C1～C6Any one of alkoxy substituted phenyl, trifluoromethyl substituted phenyl, halogenated phenyl and naphthyl, and DMFDMA represents N, N-dimethylformamide dimethyl acetal.
In the synthesis method, the 2-methyl thiochromanone compound shown in the formula I and the N, N-dimethylformamide dimethyl acetal are preferably dissolved in the solvent 1 and stirred to react for 4-6 h at the temperature of 140-150 ℃.
In the above synthesis method, the periodate compound is one of sodium periodate and periodic acid or a mixture thereof.
In the above synthesis method, the molar ratio of the 2-methylthiochromone compound to the N, N-dimethylformamide dimethyl acetal to the high-iodine compound is preferably 1:1.0 to 3.0:2.0 to 3.0.
In the above synthesis method, the solvent 1 is any one of N, N-dimethylformamide, N-dimethylacetamide, pyridine and acetonitrile, or a mixture thereof.
In the above synthesis method, the solvent 2 is a mixture of water and any one of tetrahydrofuran, N-dimethylformamide and pyridine.
The invention has the following beneficial effects:
the invention takes 2-methyl thiochromone as raw material, firstly reacts with N, N-dimethyl formamide dimethyl acetal to generate enamine compounds, the reaction system is subjected to simple post-treatment, and the reaction system is directly added with a high iodine compound to carry out redox reaction, thus obtaining the 2-aldehyde thiochromone compounds. Compared with the existing selenium dioxide oxidation method, the synthesis method of the invention has simpler post-treatment operation, higher product yield, good experimental repeatability and wide substrate application range, and simultaneously, the selenium dioxide is a B-grade inorganic extremely toxic substance, and the N, N-dimethylformamide dimethyl acetal and the high iodine compound used by the invention are relatively safer. Therefore, the invention provides a simpler and more convenient and efficient method for synthesizing the 2-aldehyde thiochromone compound, and provides a more effective material basis for corresponding thiochromone light protecting groups and related research.
Drawings
FIG. 1 is a schematic representation of the 2-aldehyde thiochromone prepared in example 11H NMR chart.
FIG. 2 is a schematic representation of the 2-aldehyde thiochromone prepared in example 113C NMR chart.
FIG. 3 is a schematic representation of the 2-formyl-3-iodothiochromone preparation of example 21H NMR chart.
FIG. 4 is a schematic representation of the 2-formyl-3-iodothiochromone preparation of example 213C NMR chart.
FIG. 5 is a schematic representation of the preparation of 2-formyl-3-phenylsulfone from example 31H NMR chart.
FIG. 6 is a drawing of the preparation of 2-formyl-3-phenylsulfone from example 313C NMR chart.
FIG. 7 is a schematic representation of the preparation of 2-formyl-3-p-trifluoromethylphenylthiochromone from example 41H NMR chart.
FIG. 8 is a schematic representation of the preparation of 2-formyl-3-p-trifluoromethylphenylthiochromone from example 413C NMR chart.
Detailed Description
The present invention will be described in further detail with reference to the following drawings and examples, but the scope of the present invention is not limited to the following examples.
Example 1
Preparation of 2-aldehyde thiochromones
Figure BDA0002833853630000031
Adding 150mg (0.85mmol) of 2-methyl thiochromone shown as formula I-1 into a 25mL round-bottom flask, adding 4.3mL of N, N-dimethylformamide to dissolve the 2-methyl thiochromone, adding 0.23mL (1.70mmol) of N, N-dimethylformamide dimethyl acetal, refluxing at 150 ℃ for 4 hours, cooling to room temperature after the reaction is finished, adding water into the reaction liquid, adding dichloromethane for separating and extracting for three times, combining organic phases, drying with anhydrous magnesium sulfate, performing suction filtration by using a sand core funnel, and evaporating the solvent under reduced pressure to obtain the enamine intermediate shown as formula II-1. The enamine intermediate of formula II-1 and 546mg (2.55mmol) of sodium periodate were charged into a 25mL round-bottomed flask, and 2.8mL of tetrahydrofuran and 2.8mL of water were added and reacted at room temperature for 2 hours. Adding a saturated sodium thiosulfate aqueous solution into the reaction solution, adding dichloromethane for separating and extracting for three times, adding a saturated sodium bicarbonate aqueous solution into an organic phase, separating and extracting for three times, combining the organic phases, drying by using anhydrous magnesium sulfate, performing suction filtration by using a sand core funnel, evaporating the solvent under reduced pressure, and performing separation by using a PE: and (3) carrying out column chromatography separation on the eluent with EA being 4:1(V/V) to obtain 103mg of 2-aldehyde thiochromone as a yellow solid compound shown as a formula III-1, wherein the total yield of the two steps is 64%. Structural characterization data are shown in fig. 1 and 2:1H NMR(400MHz,CDCl3)δ9.89(s,1H),8.49(d,J＝5.2Hz,1H),7.71–7.66(m,2H),7.60–7.56(m,1H),7.51(s,1H)；13C NMR(100MHz,CDCl3)δ189.68,181.21,147.93,136.63,133.63,132.77,132.17,128.92,128.50,127.90。
example 2
Preparation of 2-formyl-3-iodothiochromone
Figure BDA0002833853630000041
Adding 75mg (0.25mmol) of 2-methyl-3-iodothiochromone shown in formula I-2 into a 10mL round-bottom flask, adding 2.5mL of N, N-dimethylformamide to dissolve 2-methyl-3-iodothiochromone, adding 66 mu L (0.5mmol) of N, N-dimethylformamide dimethyl acetal, refluxing at 150 ℃ for 4h, cooling to room temperature after the reaction is finished, adding water into the reaction solution, adding dichloromethane, separating and extracting for three times, combining organic phases, drying with anhydrous magnesium sulfate, and performing suction filtration by using a sand core funnelAnd distilling off the solvent under reduced pressure to obtain the enamine intermediate of the formula II-2. The enamine intermediate of the formula II-2 and 159mg (0.74mmol) of sodium periodate were charged into a 10mL round-bottomed flask, and 1.3mL of tetrahydrofuran and 1.3mL of water were added and reacted at room temperature for 2 hours. Adding a saturated sodium thiosulfate aqueous solution into the reaction solution, adding dichloromethane for separating and extracting for three times, adding a saturated sodium bicarbonate aqueous solution into an organic phase, separating and extracting for three times, combining the organic phases, drying by using anhydrous magnesium sulfate, performing suction filtration by using a sand core funnel, evaporating the solvent under reduced pressure, and performing separation by using a PE: DCM: and (3) carrying out column chromatography separation on the eluent with EA being 8:1:1(V/V) to obtain 58.7mg of 2-aldehyde-3-iodothiochromone as a yellow solid compound shown in the formula III-2, wherein the total yield of the two steps is 75%. Structural characterization data see fig. 3 and 4:1H NMR(400MHz,CDCl3)δ10.22(s,1H),8.54(d,J＝5.2Hz,1H),7.73–7.69(m,2H),7.63–7.60(m,1H)；13C NMR(100MHz,CDCl3)δ195.34,176.74,144.04,136.43,132.93,130.25,129.09,128.42,126.78,111.16。
example 3
Preparation of 2-aldehyde-3-phenylthiochromone
Figure BDA0002833853630000051
Adding 250mg (0.98mmol) of 2-methyl-3-phenyl thiochromone shown in formula I-3 into a 25mL round-bottom flask, adding 4.0mLN, N-dimethylformamide to dissolve the 2-methyl-3-phenyl thiochromone, adding 0.26mL (1.96mmol) of N, N-dimethylformamide dimethyl acetal, refluxing and reacting at 150 ℃ for 6 hours, cooling to room temperature after the reaction is finished, adding water into the reaction liquid, adding dichloromethane for separating and extracting three times, combining organic phases, drying with anhydrous magnesium sulfate, performing suction filtration by using a sand core funnel, and evaporating the solvent under reduced pressure to obtain the enamine intermediate shown in formula II-3. The enamine intermediate of the formula II-3 and 631mg (2.95mmol) of sodium periodate were charged into a 25mL round-bottomed flask, and 2.3mL of tetrahydrofuran and 2.3mL of water were added and reacted at room temperature for 1 hour. Adding saturated sodium thiosulfate aqueous solution into the reaction solution, adding dichloromethane, separating and extracting for three times, adding saturated sodium bicarbonate aqueous solution into the organic phase, separating and extracting for three times, combining the organic phases, and using anhydrousAfter drying over magnesium sulfate, suction filtration was carried out using a sand core funnel, the solvent was distilled off under reduced pressure, and the residue was dried over PE: and (3) carrying out column chromatography separation on the eluent with EA being 8:1(V/V) to obtain 103mg of 2-aldehyde-3-phenyl thiochromone as a yellow solid compound shown in the formula III-3, wherein the total yield of the two steps is 72%. Structural characterization data are shown in fig. 5 and 6:1H NMR(400MHz,CDCl3)δ9.71(s,1H),8.49(d,J＝8.0Hz,1H),7.71–7.64(m,2H),7.58–7.52(m,1H),7.51–7.47(m,3H),7.40–7.35(m,2H)；13C NMR(100MHz,CDCl3)δ190.39,180.95,143.85,143.76,136.44,132.57,132.37,131.56,131.30,129.58,129.48,128.44,128.24,127.60。
example 4
Preparation of 2-formyl-3-p-trifluoromethylphenylsulfone
Figure BDA0002833853630000061
Adding 100mg (0.31mmol) of 2-methyl-3-p-trifluoromethyl phenyl thiochromone shown in formula I-4 into a 25mL round-bottom flask, adding 3.1mLN, N-dimethylformamide to dissolve 2-methyl-3-p-trifluoromethyl phenyl thiochromone, adding 83 mu L (0.62mmol) of N, N-dimethylformamide dimethyl acetal, refluxing at 150 ℃ for 4h, cooling to room temperature after the reaction is finished, adding water into the reaction liquid, adding dichloromethane for separating and extracting for three times, combining organic phases, drying with anhydrous magnesium sulfate, performing suction filtration by using a funnel sand core, and evaporating the solvent under reduced pressure to obtain the enamine intermediate of formula II-4. The enamine intermediate of formula II-4 and 267mg (1.25mmol) of sodium periodate were charged into a 25mL round-bottomed flask, and 1.6mL of tetrahydrofuran and 1.6mL of water were added and reacted at room temperature for 2 hours. Adding a saturated sodium thiosulfate aqueous solution into the reaction solution, adding dichloromethane for separating and extracting for three times, adding a saturated sodium bicarbonate aqueous solution into an organic phase, separating and extracting for three times, combining the organic phases, drying by using anhydrous magnesium sulfate, performing suction filtration by using a sand core funnel, evaporating the solvent under reduced pressure, and performing separation by using a PE: and (3) carrying out column chromatography separation on the eluent with EA being 6:1(V/V) to obtain 84mg of 2-aldehyde-3-p-trifluoromethyl phenyl thiochromone as a yellow solid compound shown in the formula III-4, wherein the total yield of the two steps is 81%. Structural characterization data are shown in fig. 7 and 8:1H NMR(400MHz,CDCl3)δ9.70(s,1H),8.48(d,J＝7.6Hz,1H),7.77(d,J＝8.0Hz,2H),7.73–7.68(m,2H),7.61–7.56(m,1H),7.53–7.49(d,J＝8.0Hz,2H)；13C NMR(100MHz,CDCl3)δ189.58,180.54,144.64,142.15,136.29,136.13(q,J＝1.3Hz),132.89,131.66,131.62,131.38,131.29,129.57,128.58,127.70,126.77(q,J＝271.1Hz),125.46(q,J＝3.7Hz)。

Claims (6)

1. a synthetic method of 2-aldehyde thiochromone compounds is characterized by comprising the following steps: dissolving a 2-methyl thiochromanone compound shown in a formula I and N, N-dimethylformamide dimethyl acetal in a solvent 1, and stirring and reacting for 3-10 h at 100-170 ℃ to obtain an enamine intermediate II; dissolving the enamine intermediate II and a high iodine compound in a solvent 2, and stirring at room temperature for 1-5 h to obtain a 2-aldehyde thiochromone compound shown in a formula III;
Figure FDA0002833853620000011
in the formula Ar1Represents phenyl, C1～C6Alkyl-substituted phenyl, C1～C6Any one of alkoxy substituted phenyl and halogenated phenyl; r1Represents hydrogen, halogen, phenyl, C1～C6Alkyl-substituted phenyl, C1～C6Any one of alkoxy substituted phenyl, trifluoromethyl substituted phenyl, halogenated phenyl and naphthyl, and DMFDMA represents N, N-dimethylformamide dimethyl acetal.
2. The method of synthesizing 2-aldehyde thiochromone compounds of claim 1, wherein: dissolving a 2-methyl thiochromanone compound shown in formula I and N, N-dimethylformamide dimethyl acetal in a solvent 1, and stirring and reacting for 4-6 h at 140-150 ℃.
3. The method of synthesizing 2-aldehyde thiochromone compounds of claim 1, wherein: the molar ratio of the 2-methyl thiochromanone compound to the N, N-dimethylformamide dimethyl acetal to the high iodine compound is 1: 1.0-3.0: 2.0-3.0.
4. The method of synthesizing 2-aldehyde thiochromone compounds of claim 1, wherein: the high iodine compound is one of sodium periodate, periodic acid or a mixture thereof.
5. The method for synthesizing a 2-aldehyde thiochromone compound according to claim 1 or 2, wherein: the solvent 1 is any one of N, N-dimethylformamide, N-dimethylacetamide, pyridine and acetonitrile or a mixture thereof.
6. The method of synthesizing 2-aldehyde thiochromone compounds of claim 1, wherein: the solvent 2 is a mixture of any one of tetrahydrofuran, N-dimethylformamide and pyridine and water.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1256688A (en) * 1997-05-15 2000-06-14 维奥恩药品公司 Process for synthesis of ribonucleotide reductase inhibitors 3-AP and 3-AMP
US20110028738A1 (en) * 2008-03-11 2011-02-03 National University Corporation NARA Institute of Science and Technology Photodissociable protective group
CN104478852A (en) * 2014-12-03 2015-04-01 天津理工大学 Novel diazo benzothiapyrone photosensitive protecting groups and synthesis method thereof
CN109879843A (en) * 2019-02-11 2019-06-14 常州制药厂有限公司 A kind of intermediate of Ba Luoshawei and the preparation method and application thereof
CN111386276A (en) * 2017-10-06 2020-07-07 盐野义制药株式会社 Stereoselective process for preparing substituted polycyclic pyridone derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1256688A (en) * 1997-05-15 2000-06-14 维奥恩药品公司 Process for synthesis of ribonucleotide reductase inhibitors 3-AP and 3-AMP
US20110028738A1 (en) * 2008-03-11 2011-02-03 National University Corporation NARA Institute of Science and Technology Photodissociable protective group
CN104478852A (en) * 2014-12-03 2015-04-01 天津理工大学 Novel diazo benzothiapyrone photosensitive protecting groups and synthesis method thereof
CN111386276A (en) * 2017-10-06 2020-07-07 盐野义制药株式会社 Stereoselective process for preparing substituted polycyclic pyridone derivatives
CN109879843A (en) * 2019-02-11 2019-06-14 常州制药厂有限公司 A kind of intermediate of Ba Luoshawei and the preparation method and application thereof

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